Paroxetine, trans (−)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl) piperidine, is a serotonin re-uptake inhibitor, and has the following molecular formula:

Paroxetine, disclosed in U.S. Pat. No. 4,007,196 (incorporated herein by reference), is an orally administered antidepressant for the treatment of depression, social anxiety disorders, obsessive compulsive disorder, panic disorder, generalized anxiety disorder and posttraumatic stress disorder. Other syndromes such as pre-menstrual syndrome (PMS) and male sexual dysfunction can also be treated with paroxetine. Paroxetine is marketed as Paxil®, and in some countries as Seroxat® by GlaxoSmithKline.
Paxil® is prescribed as oral dosage tablets containing 10 mg, 20 mg, 30 mg and 40 mg of the base equivalent of paroxetine hydrochloride. Paxil® tablets include paroxetine hydrochloride hemihydrate, dibasic calcium phosphate dihydrate, hydroxypropyl methylcellulose, magnesium stearate, polyethylene glycols, polysorbate 80, sodium starch glycolate, titanium dioxide and one or more of the following: D&C Red No. 30, D&C Yellow No. 10, FD&C Blue No. 2, FD&C Yellow No. 6.
Paxil® is also available as an oral suspension with a dosage of 10 mg of the base equivalent of paroxetine hydrochloride in a 5 mL suspension containing paroxetine hydrochloride hemihydrate, polacrilin potassium, microcrystalline cellulose, propylene glycol, glycerin, sorbitol, methyl paraben, propyl paraben, sodium citrate dihydrate, citric acid anhydrous, sodium saccharin, flavorings, FD&C Yellow No. 6 and simethicone emulsion, USP.
Although Paxil® and Seroxat® contain HPMC, it is believed that HPMC is a component of the coating in these tablets, which are probably manufactured by a direct compression method. It is believed that these tablets do not contain a binder.
Paroxetine hydrochloride exists in two solid state pseudopolymorph forms differentiated by their degree of hydration. See e.g. U.S. Pat. No. 4,721,723, incorporated herein by reference. Form I is a non hygroscopic hemihydrate and is thermodynamically more stable. Form II is a hygroscopic anhydrate. Form II converts to Form I if seed crystals of Form I are present, when exposed to humid conditions, or if subject to compression.
Commercial paroxetine tablets, such as Paxil® and Seroxat® contain paroxetine as paroxetine hydrochloride (HCl) hemihydrate. According to U.S. Pat. No. 6,113,944, having the earliest priority date of Jun. 30, 1998, a tablet containing paroxetine hydrochloride anhydrous does not exist on the market.
A potential problem with paroxetine hydrochloride anhydrous tablets is the hygroscopic nature of the anhydrous form. U.S. Pat. No. 6,113,944 discloses formulating paroxetine hydrochloride anhydrous into tablets in the absence of water, i.e., dry admixing. WO 02/069969 discloses a certain formulation of paroxetine hydrochloride anhydrous prepared by wet granulation WO 02/069969 provides only one example, which uses microcrystalline cellulose as a filler and copovidone as a binder. WO 02/069969 also discloses that microcrystalline cellulose acts as the perfect excipient. According to WO 02/069969, “[I]t is surprising that in the present invention microcrystalline cellulose acts as a perfect [excipient].” However, microcrystalline cellulose may not be such a perfect excipient.
There is a need for new formulations of paroxetine hydrochloride anhydrous and processes for their preparation.